Polygenic Hypercholesterolemia

Polygenic Hypercholesterolemia

No Results

No Results


Polygenic hypercholesterolemia is the most common cause of elevated serum cholesterol concentrations. Low-density lipoprotein cholesterol (LDL-C) elevations are moderate (140-300 mg/dL) with serum triglyceride concentrations within the reference range. However, practically speaking, the material in this article is also relevant to patients with mixed dyslipidemias with triglyceride levels of less than 350 mg/dL.

This condition is caused by a susceptible genotype aggravated by one or more factors, including atherogenic diet (excessive intake of saturated fat, trans fat, and, to a lesser extent, cholesterol), obesity, and sedentary lifestyle. The involved genes have yet to be discovered. Polygenic hypercholesterolemia is associated with an increased risk for coronary heart disease (CHD), as displayed in the image below.

In the United States, the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) guidelines are the most commonly used reference for determining therapeutic target LDL-C levels. The guidelines were first published in 1988 (ATP I), [1] with an update published in 2004. [2] The revisions and update have reflected the results of randomized placebo controlled clinical trials that have demonstrated reduced morbidity and mortality in subjects with moderate hypercholesterolemia treated with cholesterol-lowering agents, particularly (though not exclusively) statins. [3]

Low-density lipoprotein (LDL) particles are the major plasma carriers of cholesterol. Therefore, in patients with normal or minimally elevated triglyceride levels and average high-density cholesterol levels (HDL-C), the total serum cholesterol measurement can be used as a surrogate for the LDL-C level. Hypertriglyceridemia is caused by excessive numbers of very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and/or chylomicron particles; and in this situation, the total cholesterol level is not a reflection of the LDL-C level. For a simplified diagram of cholesterol metabolism, see the image below.

Elevated LDL-C concentrations may be the consequence of elevated LDL production or decreased LDL hepatic uptake. The liver is responsible for high LDL-C levels, as follows:

Overproduction of VLDL particles, which are converted to VLDL remnants or IDL particles by lipoprotein lipase and then to LDL particles by hepatic lipase (which occurs with diet high in triglycerides), or

Inefficient uptake by the LDL receptors (Diets high in saturated fat, trans fat, and cholesterol cause a reduction in LDL receptors in the liver, thus retarding LDL catabolism.) [4, 5, 6, 7]

Familial hypercholesterolemia (FH) is sometimes clinically difficult to distinguish from polygenic hypercholesterolemia unless genetic testing is performed. The presence of mutations in the following genes has most often been studied in the spectrum of familial hypercholesterolemia [8, 9] :

Gene encoding the receptor for removal of LDL-C (LDL-R), 93%

APOB gene encoding for apolipoprotein B, 5%

PCSK9 gene (proprotein convertase subtilisin kexin 9), which codes for protein responsible for degradation of LDL receptor, 2%

A case-controlled study was done in the UK to determine if LDL cholesterol gene score can help differentiate patients with polygenic and monogenic familial hypercholesterolemia. It comprised more than 600 patients with clinical FH and 3,020 control subjects. The study attempted to distinguish patients with polygenic and monogenic FH by genotyping for the 3 known genetic causes above and 12 common LDL-C raising single-nucleotide polymorphisms (SNPs). Only about 50% of patients with clinical FH had monogenic FH, although many were found to have multiple SNPs. Multiple genetic mutations were often found in those labeled as having a polygenic cause. [10]

Some patients with mixed dyslipidemias (elevations of both LDL-C and triglycerides) may have polygenic hypercholesterolemia along with some other condition such as insulin resistance or obesity that causes high triglyceride values.

United States

The guidelines of the American Heart Association and the NCEP Adult Treatment Panel III (ATP III) define hypercholesterolemia as a blood cholesterol concentration of 240 mg/dL or more. Desirable cholesterol concentrations are less than 200 mg/dL.

Based on data from the 2009-2012 National Health and Nutrition Examination Survey (NHANES), an estimated 73.5 million (31.7%) US adults aged 20 years or older has high LDL-C 130 mg/dL, but only 48.1% are treated and 29.5 % have their LDL-C controlled. A person with high LDL-C is defined as either a person whose LDL-C levels were above the LDL-C goal levels or a person who reported currently taking cholesterol-lowering medication. The proportion of adults with high LDL-C who are treated increased from 28.4% to 48.1% between the 1999-2002 and 2005-2008 study periods. Among adults with high LDL-C, the prevalence of LDL-C control increased from 14.6% to 33.2% between the periods. [11]


Serum cholesterol concentrations vary widely throughout the world. Generally, countries associated with low serum cholesterol concentrations (eg, Japan) have lower CHD event rates, while countries associated with very high serum cholesterol concentrations (eg, Finland) have very high CHD event rates. However, some populations with similar total cholesterol levels have very different CHD event rates, as would be expected given that other risk factors (eg, prevalence of smoking or diabetes mellitus) also influence CHD risk. The cholesterol levels in developing countries tend to increase as western dietary habits (McDonald’s syndrome) replace traditional diets.

Among adults, National Health and Nutrition Examination Survey data (2011-2012) showed higher LDL cholesterol level among Hispanic males (38.8%), than non-Hispanic black males (30.7%) than non-Hispanic white males (29.4%)

Elevated LDL-C is more common in females (32%) than in males (31%), based on National Health and Nutrition Examination Survey data (2011-2012).

In adults, hypercholesterolemia increases with advancing age, as shown in the image below.

The primary consequence of hypercholesterolemia is increased CHD risk. [12] Data from epidemiological studies (eg, the Multiple Risk Factor Intervention Trial and the Framingham Heart Study) show a relationship between elevated LDL-C concentrations and CHD events and CHD mortality rates. In the prestatin era, randomized clinical trials showed a clear correlation between CHD morbidity and mortality but not total mortality. The advent of the statins, medications that are more easily tolerated and substantially more powerful than older cholesterol-lowering medications, increased the likelihood of substantial LDL-C lowering (increased power). Thus, the statins showed benefits that drugs used in previous studies had not. [13]

Placebo-controlled statin trials have demonstrated not only reduced coronary morbidity and mortality in primary and secondary prevention populations, but also decreased total mortality.

The causative relationship between LDL-C levels and ischemic stroke and transient ischemic attack (TIA) was suggested by decreased cerebrovascular events in several major statin trials in which stroke was a secondary endpoint. The SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) study definitively showed that in patients who had suffered a recent stroke or TIA but who had no CHD, high-dose statin reduced the overall incidence of stroke and cardiovascular events despite a small, but statistically significant, increase in the incidence of hemorrhagic stroke. [14, 15]

Statins have revolutionized the treatment of hypercholesterolemia. Coupled with the treatment of hypertension and the use of beta-blockers, angiotensin-converting enzyme inhibitors, and aspirin, the potential for reduction of CHD events in patients with known atherosclerosis is significant.

Cholesterol reduction is certainly useful as a CHD risk-reduction strategy and for primary prevention in individuals who are at high risk for CHD and atherosclerosis.

Dietary education about a low-fat (especially saturated fat and trans fat), low-cholesterol diet is of paramount importance.

For patient education resources, see the Cholesterol Center, as well as High CholesterolCholesterol ChartsLifestyle Cholesterol ManagementCholesterol Lowering Medications, and Statins for Cholesterol.

National Cholesterol Education Program. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001. 285:2486-97. [Medline].

Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol. 2004 Aug 4. 44(3):720-32. [Medline].

Griffin BP. Statins in aortic stenosis: new data from a prospective clinical trial. J Am Coll Cardiol. 2007 Feb 6. 49(5):562-4. [Medline].

Weghuber D, Widhalm K. Effect of 3-month treatment of children and adolescents with familial and polygenic hypercholesterolaemia with a soya-substituted diet. Br J Nutr. 2008 Feb. 99(2):281-6. [Medline].

Ruiu G, Pinach S, Veglia F, et al. Phytosterol-enriched yogurt increases LDL affinity and reduces CD36 expression in polygenic hypercholesterolemia. Lipids. 2009 Feb. 44(2):153-60. [Medline].

De Castro-Oros I, Perez-Lopez J, Mateo-Gallego R, et al. A genetic variant in the LDLR promoter is responsible for part of the LDL-cholesterol variability in primary hypercholesterolemia. BMC Med Genomics. 2014 Apr 7. 7:17. [Medline]. [Full Text].

Stein EA, Raal FJ. Polygenic familial hypercholesterolaemia: does it matter?. Lancet. 2013 Apr 13. 381(9874):1255-7. [Medline].

Soutar AK, Naoumova RP. Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med. 2007 Apr. 4(4):214-25. [Medline].

Taylor A, Wang D, Patel K, et al. Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project. Clin Genet. 2010 Jun. 77(6):572-80. [Medline].

Talmud PJ, Shah S, Whittall R, et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet. 2013 Apr 13. 381(9874):1293-301. [Medline].

National Health and Nutrition Examination Survey. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/nchs/nhanes.htm. Accessed: 5/19/15.

Lewington S, Whitlock G, Clarke R, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet. 2007 Dec 1. 370(9602):1829-39. [Medline].

Carroll MD, Kit BK, Lacher DA, Yoon SSS. Total and high-density lipoprotein cholesterol in adults: National Health and Nutrition Examination Survey, 2011–2012. NCHS Data Brief. 2013;(132):1–8.

Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, Hennerici M, Rudolph AE. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006 Aug 10. 355(6):549-59. [Medline]. [Full Text].

Sniderman AD, Tsimikas S, Fazio S. The severe hypercholesterolemia phenotype: clinical diagnosis, management, and emerging therapies. J Am Coll Cardiol. 2014 May 20. 63(19):1935-47. [Medline].

Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Jun 24. 129(25 Suppl 2):S1-45. [Medline].

[Guideline] Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS)Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016 Aug 27. [Medline].

Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995 Nov 16. 333(20):1301-7. [Medline].

Scandinavian Simvastatin Survival Study. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994 Nov 19. 344(8934):1383-9. [Medline].

Pyorala K, Pedersen TR, Kjekshus J, et al. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care. 1997 Apr. 20(4):614-20. [Medline].

Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998 May 27. 279(20):1615-22. [Medline].

Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. The Post Coronary Artery Bypass Graft Trial Investigators. N Engl J Med. 1997 Jan 16. 336(3):153-62. [Medline].

Pitt B, Waters D, Brown WV, et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. Atorvastatin versus Revascularization Treatment Investigators. N Engl J Med. 1999 Jul 8. 341(2):70-6. [Medline].

Bulbulia R, Bowman L, Wallendszus K, et al. Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20,536 high-risk individuals: a randomised controlled trial. Lancet. 2011 Dec 10. 378(9808):2013-20. [Medline]. [Full Text].

Eldor R, Raz I. American Diabetes Association indications for statins in diabetes: is there evidence?. Diabetes Care. 2009 Nov. 32 Suppl 2:S384-91. [Medline]. [Full Text].

Caso G, Kelly P, McNurlan MA, Lawson WE. Effect of coenzyme q10 on myopathic symptoms in patients treated with statins. Am J Cardiol. 2007 May 15. 99(10):1409-12. [Medline].

Bargossi AM, Grossi G, Fiorella PL, Gaddi A, Di Giulio R, Battino M. Exogenous CoQ10 supplementation prevents plasma ubiquinone reduction induced by HMG-CoA reductase inhibitors. Mol Aspects Med. 1994. 15 Suppl:s187-93. [Medline].

Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J Am Coll Cardiol. 2007 Jun 12. 49 (23):2231-7. [Medline].

Writing Committee, Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly DD Jr, et al. 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2016 Jul 5. 68 (1):92-125. [Medline].

Becker DJ, Gordon RY, Halbert SC, et al. Red yeast rice for dyslipidemia in statin-intolerant patients: a randomized trial. Ann Intern Med. 2009 Jun 16. 150(12):830-9, W147-9. [Medline].

Halbert SC, French B, Gordon RY, et al. Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance. Am J Cardiol. 2010 Jan 15. 105(2):198-204. [Medline].

National Institutes of Health. Red yeast rice: An introduction. National Center for Complementary and Integrative Health Web site. Available at http://nccam.nih.gov/health/redyeastrice. Accessed: July 13, 2015.

Ricotta DN, Frishman W. Mipomersen: a safe and effective antisense therapy adjunct to statins in patients with hypercholesterolemia. Cardiol Rev. 2012 Mar-Apr. 20 (2):90-5. [Medline].

Cuchel M, Meagher EA, du Toit Theron H, Blom DJ, Marais AD, Hegele RA, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2013 Jan 5. 381 (9860):40-6. [Medline].

Jenkins DJ, Jones PJ, Lamarche B, et al. Effect of a dietary portfolio of cholesterol-lowering foods given at 2 levels of intensity of dietary advice on serum lipids in hyperlipidemia: a randomized controlled trial. JAMA. 2011 Aug 24. 306(8):831-9. [Medline].

Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012 Mar 22. 366 (12):1108-18. [Medline].

Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003 Jun. 34 (2):154-6. [Medline].

Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK. The PCSK9 decade. J Lipid Res. 2012 Dec. 53 (12):2515-24. [Medline].

Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015 May 14. 36 (19):1186-94. [Medline].

Stroes E, Colquhoun D, Sullivan D, Civeira F, Rosenson RS, Watts GF, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014 Jun 17. 63 (23):2541-8. [Medline].

Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014 May 8. 370 (19):1809-19. [Medline].

Zhang XL, Zhu QQ, Zhu L, Chen JZ, Chen QH, Li GN, et al. Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials. BMC Med. 2015 Jun 23. 13:123. [Medline].

Navarese EP, Kolodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, et al. Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis. Ann Intern Med. 2015 Jul 7. 163 (1):40-51. [Medline].

Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006 Aug 10. 355(6):549-59. [Medline].

Bays HE, McKenney J, Maki KC, et al. Effects of prescription omega-3-acid ethyl esters on non–high-density lipoprotein cholesterol when coadministered with escalating doses of atorvastatin. Mayo Clin Proc. 2010 Feb. 85(2):122-8. [Medline]. [Full Text].

Blumenthal RS, Michos ED. The HALTS trial–halting atherosclerosis or halted too early?. N Engl J Med. 2009 Nov 26. 361(22):2178-80. [Medline].

Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001 Nov 29. 345(22):1583-92. [Medline].

Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004 Apr 8. 350(15):1495-504. [Medline].

Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004 Aug 21-27. 364(9435):685-96. [Medline].

Collins R, Armitage J, Parish S, et al. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003 Jun 14. 361(9374):2005-16. [Medline].

de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004. 292(11):1307-16. [Medline].

Drazen JM, D’Agostino RB, Ware JH, Morrissey S, Curfman GD. Ezetimibe and cancer–an uncertain association. N Engl J Med. 2008 Sep 25. 359(13):1398-9. [Medline].

Garg A. Statins for all patients with type 2 diabetes: not so soon. Lancet. 2004 Aug 21-27. 364(9435):641-2. [Medline].

Goldberg RB, Jacobson TA. Effects of niacin on glucose control in patients with dyslipidemia. Mayo Clin Proc. 2008 Apr. 83(4):470-8. [Medline]. [Full Text].

Grundy SM. Can statins cause chronic low-grade myopathy?. Ann Intern Med. 2002 Oct 1. 137(7):617-8. [Medline].

Grundy SM. Statin trials and goals of cholesterol-lowering therapy. Circulation. 1998 Apr 21. 97(15):1436-9. [Medline].

Guyton JR, Slee AE, Anderson T, et al. Relationship of lipoproteins to cardiovascular events: the AIM-HIGH Trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes). J Am Coll Cardiol. 2013 Oct 22. 62(17):1580-4. [Medline]. [Full Text].

Haffner SM, Alexander CM, Cook TJ, et al. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med. 1999 Dec 13-27. 159(22):2661-7. [Medline].

Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002 Jul 6. 360(9326):7-22. [Medline].

Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008 Apr 3. 358(14):1431-43. [Medline].

Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008 Apr 3. 358(14):1431-43. [Medline].

Kastelein JJ, Bots ML. Statin therapy with ezetimibe or niacin in high-risk patients. N Engl J Med. 2009 Nov 26. 361(22):2180-3. [Medline]. [Full Text].

Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014 Jul 17. 371(3):203-12. [Medline].

LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005. 352(14):1425-35. [Medline].

Long-Term Intervention with Pravastatin in Ischaemic Disease Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998 Nov 5. 339(19):1349-57. [Medline].

Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004 Mar 3. 291(9):1071-80. [Medline].

Ornish D, Brown SE, Scherwitz LW, et al. Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial. Lancet. 1990 Jul 21. 336(8708):129-33. [Medline].

Peto R, Emberson J, Landray M, et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med. 2008 Sep 25. 359(13):1357-66. [Medline]. [Full Text].

Phillips PS, Haas RH, Bannykh S, et al. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med. 2002 Oct 1. 137(7):581-5. [Medline].

Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011 Jun 22. 305(24):2556-64. [Medline].

Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008 Sep 25. 359(13):1343-56. [Medline].

Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999 Aug 5. 341(6):410-8. [Medline].

Sempos CT, Cleeman JI, Carroll MD, et al. Prevalence of high blood cholesterol among US adults. An update based on guidelines from the second report of the National Cholesterol Education Program Adult Treatment Panel. JAMA. 1993 Jun 16. 269(23):3009-14. [Medline].

Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomi. Lancet. 2003 Apr 5. 361(9364):1149-58. [Medline].

Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002 Nov 23. 360(9346):1623-30. [Medline].

Stamler J, Daviglus ML, Garside DB, et al. Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity. JAMA. 2000 Jul 19. 284(3):311-8. [Medline].

Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009 Nov 26. 361(22):2113-22. [Medline]. [Full Text].

White HD, Simes RJ, Anderson NE, et al. Pravastatin therapy and the risk of stroke. N Engl J Med. 2000 Aug 3. 343(5):317-26. [Medline].

Zieve F, Wenger NK, Ben-Yehuda O, et al. Safety and efficacy of ezetimibe added to atorvastatin versus up titration of atorvastatin to 40 mg in patients > or = 65 years of age (from the ZETia in the ELDerly [ZETELD] study). Am J Cardiol. 2010 Mar 1. 105(5):656-63. [Medline].

Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015 Jun 18. 372(25):2387-97. [Medline].

Repatha (evolocumab). Repatha. Available at https://www.repathahcp.com/. 2016; Accessed: September 30, 2016.

Praluent (alirocumab). Praluent. Available at https://www.praluent.com/. 2016; Accessed: September 30, 2016.

Catherine Anastasopoulou, MD, PhD, FACE Associate Professor of Medicine, Sidney Kimmel Medical College of Thomas Jefferson University; Attending Endocrinologist, Department of Medicine, Albert Einstein Medical Center

Catherine Anastasopoulou, MD, PhD, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, American Society for Bone and Mineral Research, Endocrine Society, Philadelphia Endocrine Society

Disclosure: Nothing to disclose.

Goral Panchal, MD Fellow in Endocrinology, Albert Einstein Medical Center

Goral Panchal, MD is a member of the following medical societies: American College of Physicians, Tennessee Medical Association, American College of Endocrinology

Disclosure: Nothing to disclose.

Parthiv Amin, MD Fellow in Cardiovascular Medicine, East Tennessee State University, James H Quillen College of Medicine

Parthiv Amin, MD is a member of the following medical societies: American College of Cardiology, American College of Physicians, Tennessee Medical Association, Ahmedabad Medical Association, Gujarat Medical Council

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, International Society for Clinical Densitometry, Southern Society for Clinical Investigation, American College of Medical Practice Executives, American Association for Physician Leadership, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.

Steven R Gambert, MD Professor of Medicine, Johns Hopkins University School of Medicine; Director of Geriatric Medicine, University of Maryland Medical Center and R Adams Cowley Shock Trauma Center

Steven R Gambert, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for Physician Leadership, American College of Physicians, American Geriatrics Society, Endocrine Society, Gerontological Society of America, Association of Professors of Medicine

Disclosure: Nothing to disclose.

Polygenic Hypercholesterolemia

Research & References of Polygenic Hypercholesterolemia|A&C Accounting And Tax Services